SUMMARY Thromboembolic occlusions of the microvasculature are implicated in many acute ischemic conditions including stroke and myocardial infarction and may be partly responsible for the ?no-reflow? phenomenon. The fibrinolytic system and hemodynamic washout are considered the principal mechanisms for removing occlusive thromboemboli in all vascular beds, however we have shown that they have a high failure rate at the microvascular level. This may be partly due to a mechanism that we discovered and termed ?angiophagy?, whereby endothelial lamellipodia extensively envelop occluding emboli, trapping them within the vascular lumen, markedly reducing hemodynamic washout and limiting access to plasma fibrinolytic enzymes. In conditions such as stroke, it is likely that the early stage of thromboembolus engulfment is highly detrimental as it prevents distal microvascular recanalization following spontaneous reopening of large occluded vessels or after tissue plasminogen activator administration or mechanical thrombectomy. We hypothesize that pharmacologically preventing or delaying the early engulfment stages of angiophagy, can improve thromboembolic washout, and microvascular flow and viability, leading to better post-ischemic outcomes. We aim to discover signaling pathways that regulate the various stages of endothelial plasticity involved in this process, with the goal of identifying potential therapeutic targets. We will use an innovative multidisciplinary approach to elucidate these mechanisms including mutant mice, pharmacological manipulations and high resolution intravital imaging of occluded microvessels. Additionally, we will test our candidate drugs in a translational model of transient ischemic stroke. These studies are likely to advance our understanding of mechanisms of microvascular occlusion and recanalization and could identify novel targets to prevent the no- reflow phenomenon in stroke and other ischemic conditions.